Systemic fungal infections have become a major concern in the health care industry. Inadequacies of available antifungal drugs have lead some professionals to conclude that current chemotherapeutic options are insufficient to meet this growing menace. To confront this challenge, new, safe and effective antifungal drugs are needed. In our Phase I research, we demonstrated the feasibility of using fatty acid synthase (FAS) as an antifungal target by showing that the enzyme is essential to the infective process in Candida albicans. In addition, novel FAS inhibitors were discovered and characterized. In the research proposed here, we plan to continue analysis and structural modification of the compounds already in hand as well as to broaden the search for other active compounds against FAS. Experiments are planned to examine the breadth of activity, and to determine compound activity in in vivo. The ultimate objective of our work is to develop novel antifungal agents against FAS for eventual use in the treatment of disseminated fungal infections. PROPOSED COMMERCIAL APPLICATION: Successful identification of new chemotherapeutic agents for the treatment of deep-seated fungal infections would have a major impact on the physician's ability to effective care for patients suffering from systemic mycosis.